BACKGROUNDSerum creatinine concentrations (SCrs) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the intensive care unit (ICU). Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults.METHODSWe collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured 7 endogenously produced secretory solutes using liquid chromatography-tandem mass spectrometry. We computed a composite secretion score incorporating all 7 solutes and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death.RESULTSThe urine-to-plasma ratios of 6 of 7 secretory solutes were loweCenters, and the Vanderbilt O'Brien Kidney Center (NIDDK 5P30 DK114809-03). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.Despite the availability of multiple human epidermal growth factor receptor 2-targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. https://www.selleckchem.com/products/gdc-0068.html We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1-positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.Because SARS-COV2 entry into cells is dependent on angiotensin converting enzyme 2 (ACE2) and angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) increase ACE2 activity, the safety of ACEI/ARB usage during the coronavirus disease 2019 (COVID-19) pandemic is a controversial topic. To address that issue, we performed a meta-analysis following The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches of the Embase, MEDLINE, PubMed, and Cochrane Library databases identified 16 case-control studies examining the effect of ACEI/ARB on the incidence of COVID-19 and its severity. ACEI/ARB usage was associated with an increased risk of COVID-19 morbidity (odds ratio (OR) 1.20, 95% confidence interval (CI) 1.07-1.33, P=0.001) among the general population but not in a hypertensive population (OR 1.05, 95% CI 0.90-1.21, P=0.553). ACEI/ARB usage was not associated with an increased risk of COVID-19 morbidity (coefficient 1.00, 95% CI 1.00-1.00, P=0.660) when we adjusted for hypertension in the general population. ACEI/ARB usage was also not associated with an increased risk of severe illness (OR 0.90, 95%CI 0.55-1.47, P=0.664) or mortality (OR 1.43, 95%CI 0.97-2.10, P=0.070) in COVID-19 patients. Our meta-analysis revealed that ACEI/ARB usage was not associated with either the increased risk of SARS-COV2 infection or the adverse outcomes in COVID-19 patients.Growth differentiation factor 11 (GDF11), a member of the transforming growth factor β superfamily of cytokines, is a critical rejuvenation factor in aging cells. GDF11 improves neurodegenerative and neurovascular disease outcomes, increases skeletal muscle volume, and enhances muscle strength. Its wide-ranging biological effects may include the reversal of senescence in clinical applications, as well as the ability to reverse age-related pathological changes and regulate organ regeneration after injury. Nevertheless, recent data have led to controversy regarding the functional roles of GDF11, because the underlying mechanisms were not clearly established in previous studies. In this review, we examine the literature regarding GDF11 in age-related diseases and discuss potential mechanisms underlying the effects of GDF11 in regulation of age-related diseases.Metabonomics has been widely used to analyze the initiation, progress, and development of diseases. However, application of metabonomics to explore the mechanism of pulmonary arterial hypertension (PAH) are poorly reported. This study aimed to investigate the influence of atorvastatin (Ato) on metabolic pattern of rats with pulmonary hypertension.
PAH animal model was established using monocrotaline (MCT). The mean pulmonary artery pressure (mPAP) and right ventricular hypertrophy index (RVHI) were measured. The microstructure of pulmonary arterioles was observed by HE staining. Nuclear magnetic resonance was used to detect and analyze the serum metabolites. The levels of glycogen synthase kinase-3β (GSK-3β), hexokinase 2 (HK-2), sterol regulatory element-binding protein 1c (SREBP-1c), and carnitine palmitoyltransferase I (CPT-1) in the lung tissues were measured.
Ato significantly improved lung function by decreasing mPAP, RVHI, wall thickness, and wall area. Differences in metabolic patterns were observed among normal, PAH, and Ato group.